Cope Elimination

The Cope Reaction of N-oxides, which can easily be prepared in situ
from tertiary amines with an oxidant such as peracid, leads to alkenes via a thermally induced syn-elimination in
aprotic solvents.

Mechanism of the Cope Elimination

The Cope Elimination is a syn periplanar elimination in which six
electrons move in a five-membered ring according to a concerted,
thermally-induced mechanism to yield an alkene and a hydroxylamine:

The sterically demanding amine oxide function reacts preferentially with the
more easily accessible hydrogens, and often gives good selectivity favoring the
less-substituted alkene. Thus, for simple alkenes, the reaction follows the Hofmann Rule.

The following structures exemplify the stereochemical requirement for
reaching a five-membered cyclic transition state and the influence of sterically
demanding groups for some cyclic compounds:

For an early review on the Cope Elimination and similar reactions showing more
examples, please refer to DePuy and King (Chem. Rev.1960,
60, 432. DOI).

One synthetically useful exception to the general preference for more
accessible hydrogens is the reaction of substrates that bear a β-phenyl group,
or more generally speaking, an electron-withdrawing group in the β-position:

Compared with alkyl-substituted derivatives, a phenyl group provides a
100-fold rate increase. Phenyl and other electron-withdrawing groups lower the
electron density of the carbon-hydrogen bond, making the hydrogen more acidic,
and stabilizing the transition state. Computed minimal energy paths suggest that
the Cope Elimination is slightly dissymmetric and nonsynchronous, with the
H-transfer occurring slightly in advance of the other bond reorganizations (I. Komaromi, J. M. Tronchet,
J. Phys. Chem. A1997, 101, 3554).

Another interesting feature is the solvent dependence of the reaction rate.
The Cope Elimination is extraordinarily sensitive to solvent effects, and a
million-fold rate increase can be obtained going from protic to aprotic solvents.
Within aprotic solvents, decreasing polarity significantly increases the
reaction rate. The relative rate retardation for Cope Eliminations in protic
solvents arises from hydrogen bonding between the amine oxide and the solvent.
In addition, a fully solvated amine oxide in a protic solvent such as MeOH can
even be relatively more favorable energetically than the less polar
hydroxylamine, which can displace the equilibrium to favor the retro-Cope
Elimination (O. Acevedo, W. L. Jorgensen, J. Am. Chem. Soc.2006, 101,
6141):